2020: looking back on a year of ME/CFS research

2020 was an exceptional year in many ways. The coronavirus pandemic swept across the world causing more than a million deaths and forcing most developed nations into lockdown. Although COVID-19 brought havoc and despair, it also renewed scientific interest in postviral syndromes and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Hopefully, this will lead to a breakthrough in the not too distant future. In this blog post, I look back on the past year of ME/CFS research to highlight the most interesting findings of 2020.

Prevalence of pediatric ME/CFS in Chicago

The most impressive study of the year was conducted by Leonard Jason and colleagues in Chicago. They ran approximately 150.000 phone numbers to get an estimate of how prevalent ME/CFS is in young people (aged 5-17). This was the first ME/CFS prevalence study in youth that used a comprehensive community-screening followed by a complete physical examination. The results showed a high prevalence of pediatric ME/CFS of 0.75%, notably higher than the 0.42% prevalence Jason and colleagues reported in adults in 1999. Only 5% of those identified as having ME/CFS were already diagnosed with the illness. The vast majority of patients did not have a diagnosis yet. One downside of this study is that a lot of people in Chicago didn’t answer their telephone. It is unclear if this led to an overestimation of the prevalence of pediatric ME/CFS.

The economic impact of ME/CFS in Australia

In Australia, the research team of Donald Staines and Sonya Marshall-Gradisnik from Griffith University provided a preliminary estimate of the economic impact of ME/CFS. They sent out online questionnaires to ME/CFS patients who were included in their research database because they participated in previous studies. Surprisingly, almost half of the 163 patients contacted, did not meet any of the used case definitions (Fukuda criteria, Canadian Consensus Criteria, or International Consensus Criteria). This suggests that patients easily pop in and out of case definitions depending on the time that they are assessed. Of the 85 patients who did meet the case definitions, the total average annual cost per person was estimated at $75,697. The cost borne by the patient ($71,215) was much larger than healthcare costs borne by the government ($4,482). The vast majority of the cost came from lost employment from patients ($48,757).

Reduced cerebral blood flow in a large Dutch cohort

In the Netherlands, the most impressive data came from Frans Visser and Linda Van Campen, two cardiologists who are married to each other and have developed an interest in ME/CFS. Visser and Van Campen are pursuing the idea that orthostatic intolerance and reduced (cerebral) blood flow are important features of ME/CFS. They have teamed up with Peter Rowe from Johns Hopkins University, one of the pioneers of this hypothesis. In 2020, Van Campen and Visser published results of autonomic and exercise testing on a very large patient cohort. The head-up tilt test was performed on more than 400 patients and approximately 28% showed signs of postural orthostatic tachycardia. The most interesting findings, however, came from the subgroup of patients with severe ME/CFS. These patients were too ill to do a head-up tilt test, so Van Campen and Visser measured the cerebral blood flow while lying down and while sitting. The results were impressive. The reduction in cerebral blood flow in severe ME/CFS patients was 24% compared to only 1.2% in healthy controls. The authors write that the magnitude of these reductions was similar to the results of less severe ME/CFS patients during full head-up tilt testing. These findings might explain why patients with severe ME/CFS have such difficulty with simply sitting upright.  

UpTime: objectively measuring feet on the ground

There was also a small study, funded by Solve ME/CFS Initiative, that is worth mentioning. Shad Roundy and colleagues from the University of Utah have developed a sensor-based method to measure upright activity: the time that we spend with our feet on the floor including sitting, standing and walking. The authors call this measurement ‘UpTime’ and provide preliminary data that suggests it acts as an indicator of ME/CFS severity. Healthy controls had average weekly UpTimes between 30–50%. Subjects with moderate ME/CFS generally had UpTimes between 20–30% and subjects with severe ME/CFS averaged daily UpTime scores between 10–20%. The confidence intervals of the groups did not overlap, suggesting there was a clear separation.

Not all findings in 2020 have supported the reduced blood flow hypothesis though. A study on patients from the Bateman Horne Center, for example, reported no difference in postural orthostatic tachycardia between ME/CFS patients and healthy controls (which seems mostly due to a high prevalence of postural orthostatic tachycardia in the control group). The study did report increased heart rate and abnormally narrow pulse pressure in a subgroup of ME/CFS patients who have been sick for less than 4 years.

The large HLA study from Norway

Next up is a large study from Norway that looked at Human Leukocyte Antigen (HLA) alleles. HLA genes help the immune system to recognize pathogens. They have been associated with various autoimmune diseases. Several researchers have also looked for an association between HLA genes and ME/CFS but the results have been negative or conflicting. This Norwegian research team, which includes the oncologists Øystein Fluge and Olav Mella, notes that these past studies were too small. Usually, they only had about 50 patients and were therefore underpowered to detect moderate to small associations with HLA genes. To test this hypothesis appropriately, one would need a much larger sample size. And that’s exactly what this research team did. They collected data from 426 ME/CFS patients and 4511 healthy and ethnically matched controls. The results showed a small but significant association between two HLA alleles (HLA-C*07:04 and HLA-DQB1) and ME/CFS. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group. That might not seem like much but these are genetic differences that are unlikely to be a consequence of being ill or deconditioned, an uncertainty that plagues many findings in ME/CFS research. For this reason, science blogger Simon McGrath suggests that this might be “the best evidence yet that immune system problems can cause ME/CFS.” For anyone interested in learning more about this study and why its findings are important, I can highly recommend Simon’s article.

Also of interest, is a Swedish study by the research team of Jonas Bergquist. They claim to have validated the findings of Carmen Scheibenbogen on autoantibodies directed against adrenergic and muscarinic receptors in a subgroup of ME/CFS patients. However, no significant correlations were found between autoantibody levels and disease severity. The authors write that “this lack of clear correlation between antibody levels and clinical symptoms challenge the clinical relevance of autoantibodies to adrenergic and muscarinic receptors and their connection to the pathology of ME.” So not exactly a breakthrough. The Swedish team also looked at cerebrospinal fluid samples (Bergquist’s specialty) but no significant levels of autoantibodies were detected there.

Understanding post-exertional malaise

Since the 2015 report by the National Academy of Medicine, post-exertional malaise (PEM) is increasingly viewed as the hallmark symptom of ME/CFS. In 2020 there were a couple of interesting studies on PEM. The one that sparked most discussion was carried out by researchers at the National Institutes of Health. They formed focus groups and listened to patients’ experiences to better understand PEM. One of the interesting conclusions that came out of the study is the presence of a compounding effect. When focus group participants were asked to describe PEM, many stressed the importance of understanding their ‘starting point’ or ‘baseline’. They explained how successive exertion can ‘compound’ symptoms which makes it difficult to study PEM. Participants for example said they felt already worse before the start of the study because of the travel to get to the testing site. Interestingly, some participants described experiencing an adrenaline rush while doing an activity before the PEM symptoms came on. These participants described experiencing ‘adrenaline,’ ‘endorphins,’ and ‘euphoria.’ As I wrote in a previous blog post on the study, this differentiates PEM from the aches and symptoms unfit persons experience when they try to exercise more. It also makes clear that PEM is not about disliking exercise or merely some discomfort during or immediately after physical activity.

Meanwhile, the research team of Leonard Jason is working on an extensive questionnaire to adequately measure PEM. Researchers from the Workwell Foundation have confirmed that ME/CFS patients report more symptoms, such as cognitive dysfunction, after an exercise test than healthy controls. A French study with a large sample size of almost 200 ME/CFS patients looked at epidemiological and clinical factors associated with PEM severity. One of the most notable findings, in my view, is that fatigue scores were similar among PEM severity groups suggesting that these are independent factors.

Interestingly in a large international survey of patients with lingering symptoms following (suspected) COVID-19 infection, PEM was one of the most commonly reported symptoms, even though more than 200 symptoms were assessed. This suggests that SARS-CoV-2 might be one of the viruses that can trigger ME/CFS.

Provocation studies

Next up are provocation studies. These are studies that use a stressor such as physical exercise to look for biological differences between ME/CFS patients and controls. The most interesting findings were reported by the research team of James Baraniuk from Georgetown University in Washington. They used functional magnetic resonance imaging (fMRI) to measure neural activity during a memory task both before and after exercise. While exercise did not affect neural activity in healthy controls, it increased activation in certain brain regions of ME/CFS patients such as the dorsal midbrain, left operculo-insular cortex, and right middle insula. According to the authors, these regions are involved in threat assessment, pain, interoception, negative emotion, and vigilant attention. As they only emerge post-exercise, these regional differences might be involved in the mechanism of PEM. The authors also included a control group with Gulf War Illness. In this group, exercise also affected neural activity but in different ways compared to the ME/CFS group.

Another interesting provocation study was published by the Canadian team of Alain Moreau. They looked at microRNA: small molecules that help regulate gene expression after a physical stressor. The interesting thing about this study is that they didn’t use a traditional exercise test to induce PEM. Instead, they used an inflatable cuff that is applied to the arm and exerts pulsatile compression for 90 minutes. To be honest, I’m not sure if this really induces PEM but I’m happy that researchers are studying other provocation methods that are less taxing than a cardiopulmonary exercise test. Moreau and colleagues report that there are“specific microRNA expression signatures associated with ME/CFS in response to PEM induction.” It will be interesting to see if this can be replicated by other research groups.

Risk factors for developing ME/CFS

One of the most interesting papers was published at the very end of 2020. It looked at college students in Chicago who got an Epstein Barr Virus (EBV) infection. Most recovered but a small group did not and met diagnostic criteria for ME/CFS 6 months later. In this study, 23% of students with an EBV-infection went on to develop ME/CFS which is significantly higher than previous estimates (that were closer to 10%).

The most interesting part of this study, however, is that the authors collected data on the students before they got the EBV infection or developed ME/CFS. That gives us valuable information about the risk factors for developing ME/CFS. We don’t have a lot of information about this because it is very difficult to measure. Only a small subgroup of students gets an EBV infection and you can’t know in advance who will get it. That means that the researchers had to hand out questionnaires to thousands of students. In this study, approximately 4500 students completed the surveys, and 55 eventually developed ME/CFS.

The questionnaires measured symptoms and psychological aspects such as anxiety, depression, perceived stress, and coping methods. At time point 1, there were no significant differences for these outcomes between the group that went on to develop ME/CFS after EBV infection and the group that recovered after EBV infection. The authors write: “those who developed ME/CFS had more physical symptoms and immune irregularities, but not more psychological symptoms than those who recovered.” At the time of EBV infection, however, there were lots of significant differences between these groups: the group that developed ME/CFS had more depression, anxiety, and perceived stress – perhaps because they also had more physical symptoms. Hopefully, we will see more studies like this in the not too distant future.

‘Solicitous’ response: not harmful after all?

There’s one other study that I would like to highlight, mainly because it had an enormous sample size of 1356 participants. It was published by the Dutch research team that has been most assertive in pushing the cognitive-behavioral model for ME/CFS.

In a previous study, some of these authors had boldly stated that “partners’ solicitous responses and illness perceptions at the start of the therapy can negatively affect the outcome of CBT [cognitive behavioral therapy] for CFS. We emphasize the importance of addressing this in therapy.”

The term ‘solicitous response’ refers to comforting patients, showing concern or empathy for their physical condition, and encouraging them to slow down, rest, and get support from other people.So the authors were saying that this support from partners negatively affects treatment outcome and that it should be addressed in therapy. That is problematic in so many ways that I simply don’t have time to go into it all. Suffice to say that such treatment advice could have prevented ME/CFS patients from receiving empathic care from their loved ones.

In this new, larger study by some of the same authors, solicitous responses no longer negatively impacted treatment response. Hopefully, this will lay this controversial and potentially damaging hypothesis to rest.

hEDS and intracranial hypertension

One paper that received a lot of discussion on social media and ME/CFS forums was published by the research team of Björn Bragée and Bo Bertilson. They have recently set up an ME/CFS clinic in Sweden and performed an extensive examination of the patients that were referred to them, including MRI scans. In this study, they report data on a large sample of 229 ME/CFS patients.

General joint hypermobility was identified in half of the patients and one-fifth met the criteria for hypermobile type Ehlers-Danlos Syndrome (hEDS). An increased prevalence of hypermobility and hEDS in ME/CFS patients has also been reported in a preprint by Jessica Eccles and colleagues from Brighton and Sussex University Hospitals.  

Based on measurements of the optic nerve sheath diameter Bragée and colleagues also suggest an increased prevalence of intracranial hypertension in ME/CFS patients. This is in accordance with the hypothesis Mieke Hulens and colleagues are pursuing in Belgium.  

All these studies are preliminary though and vulnerable to various biases, such as lack of blinding and selection bias. They received quite a lot of critical comments on the Science for ME forum (here and here). It remains to be seen if the authors can validate their findings with more robust methods or whether associations with hEDS and intracranial hypertension are merely research hypes that will not stand the test of time.

Honorable mentions

Finally, I would like to close off with some honorable mentions. Both the research group of Julia Newton in the UK and the team by Paul Fisher in Australia are reporting abnormalities in mitochondrial function.  

The Japanese group of Yasuyoshi Watanabe performed an extensive examination of 48 ME/CFS patients. Their results suggest “a cluster of sleeprelated molecular changes as a prominent feature of ME/CFS.”

The research team of Ian Lipkin is mostly looking into the gut and the relationship between irritable bowel syndrome and ME/CFS. In a 2020 paper in PLOS One, they report an association between ME/CFS and antigen driven clonal B cell expansion.

In a study funded by ME Research UK, the Belgian team of Andrea Polli and colleagues reported levels of brain-derived neurotrophic factor (BDNF) to be higher in ME/CFS patients compared to controls. It looks like the research team will investigate this further in a future study.

When it comes to completed treatment trials there is little to report except for this Phase II trial on cyclophosphamide. It was conducted by the Norwegian team of Øystein Fluge and Olav Mella, two oncologists who entered ME/CFS research when they saw a couple of ME/CFS patients improve after receiving treatment for cancer. Fluge and Mella initially focused on rituximab, but their Phase III study failed to show effectiveness in patients with ME/CFS. In this new study, they report the results for cyclophosphamide, a medication that is frequently used as chemotherapy. The results are encouraging with half of the 40 patients responding to treatment and some reporting remission of ME/CFS at follow-up. The trial, however, was not placebo-controlled so it remains to be seen if cyclophosphamide will fare better than rituximab in a phase III trial. There is also concern that cyclophosphamide causes significant side effects.

I would like to end with a German study by Bupesh Prusty and colleagues that received a lot of discussion on social media and ME/CFS forums. The authors looked at the presence of HHV-6 in blood, isolated cells, and hair follicles of 25 ME/CFS patients and 10 controls. Unfortunately, they couldn’t find much. But there was another option the researchers were thinking of. Their experiments suggested that fluid from HHV-6 reactivated cells caused similar changes in the mitochondrial architecture of nearby non-infected cells, indicating that a transferrable factor from HHV-6 reactivated cells can induce abnormalities in other cells. They thought that something like this might be happening in ME/CFS. Maybe some part of the body that is difficult to investigate is infected and sending this factor to the rest of the body. In this paper, they report that serum of ME/CFS patients causes similar changes as those induced by HHV-6 reactivated cells. Unfortunately, the paper itself doesn’t provide much data to support all these hypotheses. It remains to be seen if these can be confirmed in larger experiments.

So, I think that’s it! If you can think of important ME/CFS studies that were released in 2020 but aren’t included in this overview, feel free to post them in the comments below. I already look forward to reading new ME/CFS research in 2021.

Happy New Year to all!  

5 thoughts on “2020: looking back on a year of ME/CFS research

  1. Ynske Jansen says:


    Hartelijk dank voor dit interessante jaaroverzicht.

    Ynske Jansen


  2. J says:

    Mentioning adrenaline with regard to PEM is interesting. In my own experience, adrenaline as well as positive excitement can “mask” energy limits, leading to overexertion/PEM because limits cannot be felt approaching.

    It is as if adrenaline temporally mobilises an artificial higher state of ability that does not correspond to actual energetic capacity and eats into substance.

    P.S. Since December 23, Prusty’s English language presentation at the September 2020 ME/CFS research congress in Germany is up on his Twitter. Among other findings, the presentation mentions a correlaton between mitochondrial defragmentation and fatigue.


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